Submissions for variant NM_000179.3(MSH6):c.10C>T (p.Gln4Ter)

gnomAD frequency: 0.00002  dbSNP: rs786201042

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162425	SCV000212772	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-13	criteria provided, single submitter	clinical testing	The p.Q4* pathogenic mutation (also known as c.10C>T), located in coding exon 1 of the MSH6 gene, results from a C to T substitution at nucleotide position 10. This changes the amino acid from a glutamine to a stop codon within coding exon 1. This mutation has been identified in patients with Lynch syndrome or colorectal/endometrial cancers (Baglietto L et al. J. Natl. Cancer Inst. 2010 Feb;102(3):193-201; Shirts BH et al. Genet. Med. 2016 10;18:974-81; Yurgelun MB et al. J. Clin. Oncol. 2017 Apr 1;35(10):1086-1095), and has been described as a founder mutation in the French Canadian population of Quebec (Castellsagué E et al. Clin. Genet. 2015 Jun:87(6):536-42). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000524100	SCV000253772	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln4*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). This variant is present in population databases (rs786201042, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 20028993, 25318681). It is commonly reported in individuals of French Canadian ancestry (PMID: 20028993, 25318681). ClinVar contains an entry for this variant (Variation ID: 183723). For these reasons, this variant has been classified as Pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000199142	SCV000266087	pathogenic	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000202232	SCV000279088	pathogenic	not provided	2022-05-04	criteria provided, single submitter	clinical testing	Reported as a founder variant in the French Canadian population (Castellsagu 2014); Observed in homozygous state in individuals with personal histories suspicious for constitutional mismatch repair deficiency (CMMR-D) syndrome (Castellsague 2014, Perez-Valencia 2020); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 28514183, 29485237, 20028993, 25980754, 25345868, 25318681, 22949379, 26845104, 28152038, 28135145, 28125075, 29750335, 30702970, 31604779, 31054147, 30322717, 32773772, 31980526, 31948886, 30787465, 27535533)
Fulgent Genetics, Fulgent Genetics	RCV002478495	SCV000611207	pathogenic	Endometrial carcinoma; Lynch syndrome 5; Mismatch repair cancer syndrome 3	2022-02-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162425	SCV000685163	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-17	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 1 of the MSH6 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over 10 individuals and families affected with Lynch syndrome (PMID: 20028993, 25318681), and an individual affected with endometrial cancer (PMID: 26845104). This variant has also been reported homozygous in a 10 year-old individual affected with colorectal cancer, which is consistent constitutional mismatch repair deficiency (PMID: 25318681). This variant has been described as a common founder mutation in the French Canadian population of Quebec (PMID: 25318681). This variant has been identified in 7/275906 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000199142	SCV000731537	pathogenic	Lynch syndrome	2022-06-28	criteria provided, single submitter	clinical testing	The p.Gln4X variant in MSH6 has been reported in >20 individuals with MSH6-associated cancers, and segregated with disease in at least 4 affected individuals from 3 families (Baglietto 2010 PMID: 20028993, Castellsague 2015 PMID: 25318681, Yurgelun 2015 PMID: 25980754, Shirts 2016 PMID: 26845104, Ghazani 2017 PMID: 28125075, Yurgelun 2017 PMID: 28135145, Carter 2018 PMID: 30322717, Tian 2019 PMID: 31054147, Yang 2019 PMID: 31604779, Perez-Valencia 2020 PMID: 32773772) and is believed to be a novel founder mutation in the French Canadian population (Castellsague 2015 PMID: 25318681). It has also been reported by other clinical laboratories in ClinVar (Variation ID: 183723) and has been identified in 0.006% (7/125024) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 4, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH6 gene is an established disease mechanism in Lynch Syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PS4, PM2_Supporting, PP1.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000202528	SCV000781779	likely pathogenic	Lynch syndrome 5	2016-11-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000202528	SCV000785255	pathogenic	Lynch syndrome 5	2017-06-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000199142	SCV000919725	pathogenic	Lynch syndrome	2017-10-06	criteria provided, single submitter	clinical testing	Variant summary: The MSH6 c.10C>T (p.Gln4X) variant results in a premature termination codon, predicted to cause a truncated or absent MSH6 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 5/270892 control chromosomes at a frequency of 0.0000185, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). The variant has been reported to cosegregate in 11 French-Canadian families and was determined to be a founder mutation. One individual was homozygous for the variant and consistent with CMMR-D phenotype (Castellsague_2014). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202232	SCV001134388	pathogenic	not provided	2023-06-08	criteria provided, single submitter	clinical testing	The MSH6 c.10C>T (p.Gln4*) variant causes the premature termination of MSH6 protein synthesis. This variant has been reported in the published literature in as one of the most common pathogenic Lynch Syndrome variants in French Canadian families in Quebec (PMID: 25318681 (2015)). This variant has also been identified in affected individuals with colorectal and lung cancers (PMIDs: 28135145 (2017), 28125075 (2017) and 20028993 (2010)). Based on the available information, this variant is classified as pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798562	SCV002042030	pathogenic	Breast and/or ovarian cancer	2023-05-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162425	SCV002535590	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-01	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000202528	SCV004018868	pathogenic	Lynch syndrome 5	2023-03-28	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
PreventionGenetics, part of Exact Sciences	RCV004528905	SCV004111871	pathogenic	MSH6-related disorder	2023-01-13	criteria provided, single submitter	clinical testing	The MSH6 c.10C>T variant is predicted to result in premature protein termination (p.Gln4*). This variant has been reported to be pathogenic for Lynch syndrome (see example: Supplemental Table 1, Yurgelun et al. 2017. PubMed ID: 28135145), and reported as a common Lynch syndrome variant in the French Canadian population of Quebec (Castellsagué et al. 2014. PubMed ID: 25318681). This variant has been identified in individuals with ovarian tumor (Table S1, Carter et al. 2018. PubMed ID: 30322717), prostate cancer (Table S1, Wu et al. 2020. PubMed ID: 31948886), glioblastoma (Yang et al. 2019. PubMed ID: 31604779), endometrial cancer (Table S1, Tian et al. 2019. PubMed ID: 31054147), and in the homozygous state in an individual with constitutional mismatch repair deficiency (Perez-Valencia et al. 2020. PubMed ID: 32773772). This variant has also been interpreted as likely pathogenic and pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/183723/). This variant is interpreted as pathogenic.
Baylor Genetics	RCV003462113	SCV004195770	pathogenic	Endometrial carcinoma	2023-05-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000199142	SCV004832154	pathogenic	Lynch syndrome	2023-09-18	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 1 of the MSH6 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over 10 individuals and families affected with Lynch syndrome (PMID: 20028993, 25318681), and an individual affected with endometrial cancer (PMID: 26845104). This variant has also been reported homozygous in a 10 year-old individual affected with colorectal cancer, which is consistent constitutional mismatch repair deficiency (PMID: 25318681). This variant has been described as a common founder mutation in the French Canadian population of Quebec (PMID: 25318681). This variant has been identified in 7/275906 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202232	SCV000257203	likely pathogenic	not provided		no assertion criteria provided	research
OMIM	RCV000202528	SCV000257496	pathogenic	Lynch syndrome 5	2015-06-01	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353573	SCV000592561	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Gln4* variant was identified in ClinVar (classified as pathogenic by Ambry Genetics, Invitae, GeneDx, and the University of Washington Department of Laboratory Medicine and as likely pathogenic by Mayo Clinic Genetic Testing Laboratories), COSMIC, COGR (classified as pathogenic by a clinical laboratory), and UMD (1x with a causal classification). This variant was identified in the genome Aggregation Database (beta, October 19th 2016) in 5 of 276350 chromosomes (freq. 0.00002). The variant was not found in dbSNP, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, InSiGHT Colon Cancer Gene Variant Database (LOVD), Zhejiang Colon Cancer Database (LOVD), 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium database. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The p.Gln4* variant is predicted to lead to a premature stop codon at position 4, which is predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MSH6 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. A study by Castellsague (2015) suggests the variant is a novel founder mutation in the French Canadian population. The mutation co-segregated with cancer in 15 of 23 carriers and confers a major risk to develop EC (endometrial cancer). All available tumours from carrier individuals showed MSI and IHC loss of MSH6 protein. In addition, the mutation was found in 16 samples in a control population of 6433 newborns in Quebec (~1/400). The variant was also identified by our laboratory in 2 individuals with endometrial and uterine cancer. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Institute of Human Genetics, Medical University Innsbruck	RCV001254934	SCV001431025	pathogenic	Mismatch repair cancer syndrome 1	2020-05-06	no assertion criteria provided	research